ABSTRACT: Bipolar disorder is a severe heritable psychiatric illness affecting 1% of the general population. The age of onset is generally in the late teenage years or early adulthood. Very little is known about specific risk factors that influence the incidence and age of onset of this disorder. In 1988 the NIMH established a Genetics Initiative in bipolar disorder with the goal of identifying susceptibility genes;this collaboration has identified several hundred families with multiple cases of bipolar disorder. As three of the initial collaborating sites (Indiana University, Johns Hopkins University, and Washington University at St Louis) we are now proposing to assess and follow adolescents, ages 12 -18 years, in these and similar families. This "at risk" group will be compared to a matched set of community comparison subjects. Three hundred study subjects and three hundred controls will be studied using established diagnostic instruments (KSADS- PL) for the adolescents and the parents (DIGS). Other instruments to assess behavior, temperament, family environment, and substance use will be employed. DNA will also be collected. The data will be stored in a database developed to facilitate longitudinal studies of clinical variables. Analyses will compare potential risk factors among the high risk group and the controls. Follow-up of the high risk group will begin in the second year of the study. It is hypothesized that three groups will be identified: 1) adolescents with behavioral symptoms or disorders who will manifest early-onset bipolar disorder;2) adolescents with anxiety symptoms or disorders who will manifest later-onset bipolar disorder;and 3) adolescents with minor mood symptoms or disorders who will manifest later-onset unipolar or bipolar disorder. All subjects will be characterized on the three dimensions of behavioral, anxiety, and mood symptoms;intermediate outcomes and major mood diagnoses will be evaluated in relation to baseline dimensional ratings. The ethical implications of this research will be studied by examining the effects of participation and any effect on self-esteem due to high risk status as well as the implications of the collections and potential use of genetic data for prediction of risk within families. Clinical data and DNA will be shared with the scientific community.